This project is a combination of a clinical trial of infusions of autologous anti-CD19 chimeric-antigen-receptor-transduced T cells and laboratory experiments performed on cells obtained from patients that received infusions of the chimeric-antigen-receptor-transduced T cells. During 2012 this project resulted in a Plenary Paper published in Blood entitled B-cell Depletion and Remissions of Malignancy Along With Cytokine-associated Toxicity in a Clinical Trial of Anti-CD19 Chimeric-antigen-receptor-transduced T cells. The project also resulted in abstracts that were presented as an oral presentation at the most important hematology meeting in the world, the Annual Meeting of the American Society of Hematology in both 2011 and 2013. The rest of this section summarizes the project. New therapies are needed for chemotherapy-resistant B-cell malignancies. Adoptive transfer of T cells genetically-engineered to express chimeric antigen receptors (CARs) that specifically recognize the B-cell antigen CD19 is a promising new approach for treating B-cell malignancies. We are conducting a clinical trial in which patients receive infusions of autologous T cells that are transduced with gamma-retroviruses encoding an anti-CD19 CAR. The CAR is made up of the variable regions of an anti-CD19 antibody, a portion of the CD28 molecule, and a portion of the CD3-zeta molecule. Our clinical protocol consists of cyclophosphamide plus fludarabine chemotherapy followed by an infusion of anti-CD19-CAR-transduced T cells. We have treated 21 patients on this clinical trial. The patients had chronic lymphocytic leukemia (CLL) or non-Hodgkin lymphoma. Anti-CD19-CAR-transduced T cells that specifically recognized CD19-expressing target cells were produced for all patients. The clinical trial has evolved over its 5-year history; the method of cell preparation has changed, exogenous high-dose IL-2 has been eliminated, and the dose of chemotherapy given prior to CAR T-cell infusions has been reduced drastically. Of the most recent 9 patients treated on the current version of the protocol, 1 has an ongoing complete remission, 5 obtained partial remissions, and 3 had progressive lymphoma. Many patients on this trial have had depletion of normal B cells patients have died. This B-cell depletion lasted for up to 18 months. Because of the long duration of B-cell depletion, it cannot be attributed to the chemotherapy that the patients received. For example, a patient with follicular lymphoma had a normal level of polyclonal blood B cells before treatment on our protocol. Six months after treatment, he had a blood B cell count of 1 per microliter (normal range 61-321 B cells per microliter). A patient with CLL had a regression of adenopathy in the first 32 days after chemotherapy and CAR-transduced T cell administration. CAR-transduced cells were detected in the blood of all 8 patients by quantitative PCR. The percentage of peripheral blood mononuclear cells (PBMC) containing the CAR gene varied widely. At early time-points after infusion, CAR-expressing T cells constituted up to 66 percent of all blood T cells. Patients had significant toxicities during the first 10 days after CAR-transduced T cell infusion. The most prominent toxicity were hypotension and neurological toxicity. These results demonstrate that CAR-expressing T cells can specifically eliminate targeted cells and cause significant cytokine-mediated toxicity in humans. Current efforts are aimed at evaluating low-dose chemotherapy regimens administered before anti-CD19 CAR T cells.